Throughout this application, various references are cited in parentheses to describe more fully the state of the art to which this invention pertains. The disclosure of these references is hereby incorporated by reference in their entirety into the present-disclosure.
Schizophrenia can be broadly defined as any of a group of psychotic disorders usually characterized by withdrawal from reality, illogical patterns of thinking, delusions, and hallucinations, and accompanied in varying degrees by other emotional, behavioral, or intellectual disturbances. In addition to the behavioral abnormalities, several post-mortem and in-vivo imaging studies of schizophrenic brains have described a number of structural defects, including loss of nerve fibers and synaptic markers, a reduced size and number of nerve cells, aberrant distribution of nerve cells, and ventricular enlargement (Volk, Austin, Pierri Sampson and Lewis, American Journal of Psychiatry 2001, 158: 256-265: Woo, Whitehead, Melchitzky and Lewis, Proceedings of the National Academy of Science U.S.A. 1998, 95: 5341-5346; Chua and McKenna. British Journal of Psychiatry 1995, 166: 563-582; Lewis and Levitt, Annual Review of Neuroscience 2002, 25:409-432; Harrison, P. J. 1999, Brain 122; 593-624).
Schizophrenia is associated with dopamine imbalances in the brain. It is believed that schizophrenia may be caused by genetic, other biological, and psychosocial factors. A number of epidemiological, postmortem and in-vivo imaging studies have indicated that early developmental injury and consequent defective cerebral cortical organization may underlie the adult manifestation of schizophrenic symptoms (Chua and McKenna, British Journal of Psychiatry 1995,166: 563-582; Marenco and Weinberger, Developmental Psychopathology 2000, 12: 501-527).
While animal models have been developed to represent some features of schizophrenia, none have shown any structural neuropathological features similar to those described in post-mortem brains of schizophrenic patients (Kokkinidis and Anisman, Psychological Bulletin 1980, 88: 551-579; Lipska, Jaskiw and Weinberger, Neuropsychopharmacology 1993, 9: 67-75; Uehara, Tanii, Sumlyoshi and Kurachi, Brain Research 2000, 860: 77-86).
U.S. Pat. No. 6,549,884 discloses an animal model exhibiting certain behaviors associated with human schizophrenia. A neurotoxin is used to induce neonatal lesions of the ventral hippocampus in animals that have not yet reached puberty (Lipska, Jaskiw and Weinberger, Neuropsychopharmacology 1993, 9: 67-75). This model is limited in that only behavioral abnormalities consistent with enhanced mesolimbic dopamine hyper-responsivity to environmental stress or pharmacological challenge are manifested in post-pubertal life. This model does not show any structural changes described in post-mortem or in-vivo examinations of schizophrenic brains. Furthermore, the lesion inflicted bilaterally in the ventral hippocampus in the prepubescent animal persists in adulthood as large, permanent structural damage to the ventral hippocampal area therefore precluding behavioral and cognitive testing involving intact hippocampal circuitry.
Recently, a modified method of neonatal ventral hippocampal lesioning has been described (Lipska Halim, Segal and Weinberger, Journal of Neuroscience 2002, 22: 2835-2842). This method produces animals showing certain behavioral features of enhanced post-pubertal emergence of dopamine hyper-responsitivity with apparently normal ventral hippocampus Nevertheless, the resultant animals do not show any neuropathological abnormalities of schizophrenia.
Presently, none of the animal models used in schizophrenia research show any neuropathological features of the disease. It would therefore be beneficial to provide a schizophrenia animal model that overcomes the limitations of currently used models. More specifically, it would be useful to establish an animal model of schizophrenia that exhibits neuropathological and behavioral features of human schizophrenia with apparently intact thalamic, hippocampal, cortical and subcortical circuits similar to that seen In schizophrenic patients. A desirable animal model would exhibit both neuropathological and behavioral features closely resembling the disease in humans and prove useful for the identification of pharmaceutical compounds for their potential antipsychotic property and effects on cognitive function. Such a model could also be employed in studies to determine the mechanisms underlying the manifestation of behavioral and cognitive symptoms of schizophrenia and to Identify potential molecular targets to treat schizophrenic symptoms.